Preparation method of 3-(hydroxyethyl piperazine)-2-hydroxy propanesulfonic acid

Abstract

The invention belongs to the technical field of organic compounds, and particularly relates to a preparation method of 3-(hydroxyethyl piperazine)-2-hydroxy propanesulfonic acid. The preparation method comprises the following steps: uniformly mixing hydroxyethyl piperazine and sodium 3-chloro-2-hydroxypropanesulfonate, adding a salt-forming agent to carry out substitution reaction, and after the reaction is finished, sequentially carrying out acidification and desalination to prepare an HEPPSO aqueous solution; and drying the aqueous solution of the HEPPSO to prepare the 3-(hydroxyethyl piperazine)-2-hydroxy propanesulfonic acid. By designing a synthetic route, the problems that an existing 3-(hydroxyethyl piperazine)-2-hydroxypropanesulfonic acid synthetic method is harsh in condition, tedious in operation and unstable in yield are solved.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compound synthesis, and particularly relates to a preparation method of 3-(2-hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid. Background Art

[0002] 3-(2-hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid, abbreviated as HEPPSO, is a commonly used pH buffer in laboratories, and often provides a stable pH environment for experiments such as cell culture, enzyme activity determination, and protein purification. The optimal pH buffering range is 7.4 - 8.2. Its zwitterionic structure (containing a sulfonic acid group and a piperazine ring) enables it to both bind H + and release H + , forming a dynamic equilibrium and providing a stable pH environment. Compared with traditional buffers such as bicarbonate, HEPPSO does not require a CO 2 environment and is also suitable for relatively open culture systems.

[0003] Currently, the synthesis route of HEPPSO is mainly a two-step reaction. In the first step, nucleophilic substitution reaction of 2-hydroxyethylpiperazine with 2-bromoacetic acid under the action of a basic catalyst yields an intermediate. In the second step, the intermediate reacts with propanesulfonyl chloride for sulfonation reaction to obtain the HEPPSO product. In this synthesis route, 2-bromoacetic acid is highly corrosive, propanesulfonyl chloride itself is unstable and prone to hydrolysis, and there are competitive reactions between the hydroxyl group and secondary amino group of 2-hydroxyethylpiperazine. Therefore, the synthesis conditions of this synthesis route are relatively harsh, the operation is cumbersome, and the yield is unstable. Summary of the Invention

[0004] The purpose of the present invention is to provide a preparation method of 3-(2-hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid to solve the problems of harsh synthesis conditions, cumbersome operation, and unstable yield in the existing preparation methods.

[0005] To achieve the above purpose, the technical solution adopted by the present invention is: The preparation method of 3-(2-hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid according to the present invention: Mix 2-hydroxyethylpiperazine with sodium 3-chloro-2-hydroxypropanesulfonate, add a salt-forming agent for substitution reaction. After the reaction is completed, acidification and desalting are carried out in sequence to obtain an aqueous solution of HEPPSO; the aqueous solution of HEPPSO is dried to obtain 3-(2-hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid.

[0006] Among them: The salt-forming agent is sodium hydroxide. Sodium hydroxide plays a role in neutralizing the generated product HCL to obtain NaCl; promoting the reaction to proceed in the positive direction and increasing the reaction conversion rate.

[0007] When mixing, the pH is controlled at 7 - 8; during the substitution reaction, the pH is controlled at 8 - 11.

[0008] The substitution reaction temperature is 60~80°C, and the substitution reaction time is 4~8 h.

[0009] The molar ratio of hydroxyethylpiperazine, sodium 3-chloro-2-hydroxypropanesulfonate to the salt-forming agent is 1:1:(1~1.05).

[0010] The reagent used for acidification is hydrochloric acid, and the acidification pH is 5~5.5.

[0011] The acidification temperature is 25~35°C.

[0012] The method used for desalting is electrodialysis.

[0013] During desalting, when the sodium ion content < 200 ppm, desalting is completed.

[0014] The drying method is spray drying.

[0015] The reaction equation of the present invention is as follows:

[0016] The beneficial effects of the present invention are as follows: (1) The separation of intermediates and the sulfonation step are omitted, avoiding the yield loss caused by multiple purifications. No sulfonation reagent is required. The original synthesis route needs to use propanesulfonyl chloride (which is easy to hydrolyze and requires low-temperature conditions). The present invention directly conducts a one-step reaction between sodium 3-chloro-2-hydroxypropanesulfonate and hydroxyethylpiperazine, simplifying the reaction conditions; by adding sodium hydroxide to convert HCl into NaCl, the reaction is promoted to proceed in the positive direction, improving the yield of the final product.

[0017] (2) The use of highly toxic reagents is avoided. There is no need to use 2-bromoacetic acid (strongly corrosive and carcinogenic) and propanesulfonyl chloride (irritating and easy to hydrolyze), and sodium 3-chloro-2-hydroxypropanesulfonate (high stability and low toxicity) is used instead, significantly reducing the safety risk and protection cost. The generation of harmful by-products is reduced: The original synthesis route will produce bromine-containing wastewater, which requires strict post-treatment; the by-products of the present invention are mainly sodium chloride, and the post-treatment is simple, being more environmentally friendly.

[0018] (3) In the existing route, hydroxyethylpiperazine contains two active groups, namely a hydroxyl group and a secondary amino group. When reacting with 2-bromoacetic acid, both groups will competitively attack 2-bromoacetic acid, resulting in substitution reactions of the hydroxyl group or the secondary amino group respectively, and generating multi-substituted by-products. In the present invention, sodium 3-chloro-2-hydroxypropanesulfonate is used as the reactant. The chlorine atom in its structure acts as a leaving group, forming a spatial pre-orientation effect with the adjacent hydroxyl group. Due to the steric hindrance and electronic effect of the hydroxyl group, the chlorine atom can only be specifically attacked by the secondary amino group of hydroxyethylpiperazine, thus avoiding the competitive reaction involving the hydroxyl group, ensuring a single substitution site, and inhibiting the formation of multi-substituted by-products. In addition, NaOH is added in the present invention and the pH is controlled to be 8-11. NaOH deprotonates the secondary amino group of hydroxyethylpiperazine, enhancing its nucleophilicity and promoting the substitution of the chlorine atom in sodium 3-chloro-2-hydroxypropanesulfonate. In addition, strictly controlling the pH at 8-11 is to ensure that the secondary amino group remains deprotonated and to avoid excessive ionization of the sulfonic acid group, thereby effectively avoiding side reactions and ultimately increasing the yield of 3-(hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid.

[0019] (4) The traditional route requires an excess of propanesulfonyl chloride to ensure the sulfonation efficiency, while the present invention does not require additional sulfonation reagents, reducing the consumption of raw materials. The chlorine atom in the molecule of sodium 3-chloro-2-hydroxypropanesulfonate acts as a leaving group, and the sulfonic acid group is directly retained in the product. Compared with the traditional route (where the bromine atom in bromoacetic acid is discarded), since the mass of the bromine atom is greater than that of the chlorine atom, in large-scale production, the high atom utilization rate of the present invention will be further amplified, significantly improving the production economy.

[0020] (5) After the reaction solution is acidified and purified by electrodialysis, a relatively pure aqueous solution of HEPPSO can be directly obtained. The impurities are completely removed, and no subsequent operations such as solvent purification are required, further reducing the post-treatment steps, reducing the loss of 3-(hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid, and ensuring a high and stable yield in large-scale production. Description of the Drawings

[0021] Figure 1 It is the infrared spectrum of 3-(hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid in Example 1. Detailed Embodiments

[0022] The present invention will be specifically described and illustrated below in conjunction with the embodiments.

[0023] Example 1 Add 250 g of pure water to the reaction flask, add 205 g of sodium 3-chloro-2-hydroxypropanesulfonate (purity 96 wt%), and stir until completely dissolved. Then heat up to 75 °C, and dropwise add 130 g of hydroxyethylpiperazine (purity 99 wt%) thereto, maintain stirring, and control the pH to be 7-8. Continue to dropwise add 80 g of 50 wt% liquid alkali, maintain the pH value at 8-9, and stir and react for 6 h to obtain the reaction solution.

[0024] After the reaction solution was cooled to 35 °C, 32 wt% hydrochloric acid was added dropwise, and the pH was adjusted to 5.2 for acidification; then electrodialysis was used for desalination until the sodium ion content was < 200 ppm to complete desalination, and an aqueous solution of HEPPSO was prepared.

[0025] An aqueous solution of HEPPSO was taken, and after potentiometric titration, 225 g of 3-(2-hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid was obtained by calculation of the pure form, and the yield was 84.82%. The aqueous solution of HEPPSO was spray-dried to obtain a solid product of 3-(2-hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid. The solid product was detected by infrared spectroscopy, and the infrared spectrum is shown in Figure 1 , confirming the obtained 3-(2-hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid.

[0026] Example 2 250 g of pure water was added to a reaction flask, 205 g of sodium 3-chloro-2-hydroxypropanesulfonate (purity 96 wt%) was added, and the mixture was stirred until completely dissolved; then the temperature was raised to 80 °C, and 130 g of 2-hydroxyethylpiperazine (purity 99 wt%) was added dropwise thereto, stirring was maintained, and the pH was controlled at 8 - 9; 84 g of 50 wt% liquid caustic soda was continuously added dropwise, the pH value was maintained at 9 - 10, and the mixture was stirred and reacted for 8 h to obtain a reaction solution.

[0027] After the reaction solution was cooled to 25 °C, 32 wt% hydrochloric acid was added dropwise, and the pH was adjusted to 5.5 for acidification; then electrodialysis was used for desalination until the sodium ion content was < 200 ppm to complete desalination, and an aqueous solution of HEPPSO was prepared.

[0028] An aqueous solution of HEPPSO was taken, and after potentiometric titration, 230 g of 3-(2-hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid was obtained by calculation of the pure form, and the yield was 86.70%. The aqueous solution of HEPPSO was spray-dried to obtain a solid product of 3-(2-hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid. The solid product was detected by infrared spectroscopy, and the test results confirmed the obtained 3-(2-hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid.

[0029] Example 3 250 g of pure water was added to a reaction flask, 205 g of sodium 3-chloro-2-hydroxypropanesulfonate (purity 96 wt%) was added, and the mixture was stirred until completely dissolved; then the temperature was raised to 60 °C, and 130 g of 2-hydroxyethylpiperazine (purity 99 wt%) was added dropwise thereto, stirring was maintained, and the pH was controlled at 9 - 10; 83 g of 50 wt% liquid caustic soda was continuously added dropwise, the pH value was maintained at 10 - 11, and the mixture was stirred and reacted for 4 h to obtain a reaction solution.

[0030] After the reaction solution was cooled to 32 °C, 32 wt% hydrochloric acid was added dropwise to adjust the pH to 5 for acidification. Then, electrodialysis was used for desalination until the sodium ion content was <200 ppm to complete desalination, and an aqueous solution of HEPPSO was prepared.

[0031] An aqueous solution of HEPPSO was taken, and after potentiometric titration, 233 g of 3-(2-hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid was obtained by calculation of the pure product, and the yield was 87.83%. The aqueous solution of HEPPSO was spray-dried to obtain a solid product of 3-(2-hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid. The solid product was detected by infrared spectroscopy, and the detection results confirmed the obtainment of 3-(2-hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid.

[0032] Comparative Example 1 Sodium hydroxide was not added, and the remaining steps were the same as in Example 1. After detection, 3-(2-hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid could not be obtained.

[0033] Comparative Example 2 First step of substitution reaction: 147 g of 2-hydroxyethylpiperazine and 138 g of 2-bromoacetic acid were subjected to a substitution reaction under the action of a catalyst, and the remaining operating steps were the same as in Example 1 to obtain an intermediate. Second step of sulfonation reaction: Cooled to 0 °C in an ice bath, 10 g of triethylamine and 143 g of propanesulfonyl chloride were added dropwise to the intermediate in sequence, and then the temperature was raised to 9 °C and stirring was continued for 2.2 h for the sulfonation reaction. After the reaction was completed, the organic phases were combined and washed successively with 5 wt% sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate; successively filtered, concentrated under reduced pressure, and purified by column chromatography (eluent: dichloromethane / methanol = 20:1 → 10:1), and 115.3 g of 3-(2-hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid was obtained by calculation of the pure product, and the yield was 42.97%.

[0034] Evaluation of implementation effect Examples 1 to 3 of the present invention have the advantages of simpler operation (without complex operations such as low temperature), simpler post-treatment, and higher yield.

[0035] In Comparative Example 1, pure product could not be obtained without adding sodium hydroxide; in Comparative Example 2, propanesulfonyl chloride was prone to hydrolysis, the reaction needed to strictly control the low temperature condition, and 2-bromoacetic acid had strong corrosiveness and carcinogenicity, and the operation needed to be strictly isolated, the process was more cumbersome, and the yield of the final product in Comparative Example 2 was lower.

Claims

1. A method for preparing 3-(hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid, characterized in that: Hydroxyethylpiperazine and sodium 3-chloro-2-hydroxypropanesulfonate are mixed, and a salt-forming agent is added to carry out a substitution reaction. After the reaction is completed, the mixture is acidified and desalted in sequence to obtain a HEPPSO aqueous solution; the HEPPSO aqueous solution is dried to obtain 3-(hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid.

2. The method for preparing 3-(hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid according to claim 1, characterized in that: The salt-forming agent is sodium hydroxide.

3. The method for preparing 3-(hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid according to claim 1, characterized in that: During mixing, the pH is controlled at 7-10; during substitution reaction, the pH is controlled at 8-11.

4. The method for preparing 3-(hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid according to claim 1, characterized in that: The substitution reaction temperature is 60~80℃, and the substitution reaction time is 4~8h.

5. The method for preparing 3-(hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid according to claim 1, characterized in that: The molar ratio of hydroxyethylpiperazine, sodium 3-chloro-2-hydroxypropanesulfonate and the salt-forming agent is 1:1:(1-1.05).

6. The method for preparing 3-(hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid according to claim 1, characterized in that: The reagent used for acidification is hydrochloric acid, and the acidification pH is 5~5.

5.

7. The method for preparing 3-(hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid according to claim 6, characterized in that: The acidification temperature is 25~35℃.

8. The method for preparing 3-(hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid according to claim 1, characterized in that: The method used for desalination is electrodialysis.

9. The method for preparing 3-(hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid according to claim 8, characterized in that: During desalination, when the sodium ion content is less than 200ppm, desalination is completed.

10. The method for preparing 3-(hydroxyethylpiperazine)-2-hydroxypropanesulfonic acid according to claim 1, characterized in that: The drying method is spray drying.

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